Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions?

Figures & data

Table 1 Demographic and baseline characteristics of the study population

Variable	Part 1 (glimepiride)		Total	Part 2 (rosuvastatin)		Total
	G-GR	GR-G		R-GR	GR-R
Total population, n	12	12	24	11	11	22
Age (years)	25.3±3.9 (21.0–34.0)	26.4±3.5 (22.0–34.0)	25.8±3.7 (21.0–34.0)	26.0±6.2 (20.0–40.0)	25.3±5.1 (22.0–40.0)	25.6±5.5 (20.0–40.0)
Body weight (kg)	69.6±8.6 (56.6–85.0)	68.0±5.4 (59.5–75.1)	68.8±7.1 (56.6–85.0)	66.7±5.2 (57.9–74.8)	68.0±9.4 (56.8–82.9)	67.4±7.4 (56.8–82.9)
Body mass index (kg/m^2)	22.4±2.1 (19.7–24.9)	22.9±1.7 (20.2–24.9)	22.6±1.9 (19.7–24.9)	22.3±1.2 (20.3–24.6)	21.9±2.4 (19.1–24.8)	22.1±1.9 (19.1–24.8)
Genotyping subpopulation, n	11	11	22	7	9	16
Age (years)	24.5±2.9 (21.0–30.0)	26.1±3.5 (22.0–34.0)	25.3±3.3 (21.0–34.0)	25.6±6.8 (20.0–40.0)	25.4±5.6 (22.0–40.0)	25.5±5.9 (20.0–40.0)
Body weight (kg)	69.8±9.0 (56.6–85.0)	67.3±5.2 (59.5–73.7)	68.6±7.3 (56.6–85.0)	66.7±4.5 (61.0–73.7)	67.7±9.3 (56.8–82.9)	67.2±7.4 (56.8–82.9)
Body mass index (kg/m^2)	22.4±2.2 (19.7–24.9)	22.7±1.7 (20.0–24.9)	22.6±1.9 (19.7–24.9)	22.5±1.3 (21.2–24.6)	21.8±2.3 (19.1–24.8)	22.1±1.9 (19.1–24.8)

Notes: The data are expressed as mean ± SD (min–max). The sequence G-GR consisted of 7-day cycles of treatment G and GR; a 4 mg glimepiride tablet once per day (treatment G), and co-administration of a 4 mg glimepiride tablet and a 20 mg rosuvastatin tablet once per day (treatment GR). Sequence R-GR consisted of 7-day cycles of treatment R and treatment GR; a 20 mg rosuvastatin tablet once per day (treatment R). The P-values (not shown) between the two groups in each part were calculated using the Wilcoxon rank-sum test. There were no statistically significant differences in age, body weight, and body mass index of the total population and genotyping subpopulation between the two groups.

Abbreviation: SD, standard deviation.

Table 2 PK parameters of glimepiride after the administration of multiple oral doses of 4 mg glimepiride once per day (treatment G) and coadministration of 4 mg glimepiride and 20 mg rosuvastatin once per day (treatment GR) in healthy volunteers

PK parameters	Glimepiride (G) (n=22)	Glimepiride + rosuvastatin (GR) (n=22)	Geometric mean ratio (GR/G)
			Point estimate	90% confidence interval
Cmax,ss (ng/mL)	173.7±55.4	180.5±65.3	1.03	0.91–1.16
AUCτ,ss (ng h/mL)	971.3±280.7	1,028.0±398.4	1.03	0.94–1.14
t1/2 (h)	13.3±12.3	11.7±5.0
tmax,ss (h)	4.0 (2.0–6.0)	3.0 (1.5–5.0)
CL/F (L/h)	4.5±1.3	4.4±1.5

Notes: The values are presented as mean ± SD, except for the t_max,ss, which is presented as the median (range).

Abbreviations: C_max,ss, maximum plasma concentration of the drug at steady state; AUC_τ,ss, area under the plasma concentration–time curve during the dose interval at steady state; t_1/2, elimination half-life; t_max,ss, time to C_max,ss; CL/F, apparent total clearance; PK, pharmacokinetic; SD, standard deviation.

Figure 1 Mean plasma concentration profiles of glimepiride at steady state.

Notes: (A) Linear scale; (B) semi-logarithmic scale. Error bars denote standard deviations.

Table 3 PK parameters of rosuvastatin after administration of multiple oral doses of 20 mg rosuvastatin once per day (treatment R) and coadministration of 4 mg glimepiride and 20 mg rosuvastatin once per day (treatment GR) in healthy volunteers

PK parameters	Rosuvastatin (R) (n=22)	Glimepiride + rosuvastatin (GR) (n=22)	Geometric mean ratio
			Point estimate	90% confidence interval
Rosuvastatin
Cmax,ss (ng/mL)	29.1±19.9	29.9±12.7	1.12	0.98–1.27
AUCτ,ss (ng h/mL)	225.7±95.4	208.3±72.9	0.94	0.86–1.03
t1/2 (h)	13.9±9.8	11.8±3.4
tmax,ss (h)	4.5 (1.5–6.0)	4.0 (2.0–6.0)
CL/F (L/h)	103.1±40.6	107.3±35.9
N-Desmethyl rosuvastatin
Cmax,ss (ng/mL)	6.2±3.8	5.4±1.8	0.96	0.84–1.10
AUCτ,ss (ng h/mL)	47.2±18.6	38.2±12.2	0.83	0.74–0.93
t1/2 (h)	11.2±14.7	7.7±3.3
tmax,ss (h)	4.5 (1.5–5.0)	4.0 (2.0–6.0)
CL/F (L/h)	506.7±261.5	594.8±247.8

Notes: The values are presented as mean ± SD.

Abbreviations: C_max,ss, maximum plasma concentration of the drug at steady state; AUC_τ,ss, area under the plasma concentration–time curve during the dose interval at steady state; t_1/2, elimination half-life; t_max,ss, time to C_max,ss; CL/F, apparent total clearance; PK, pharmacokinetic; SD, standard deviation.

Figure 2 Mean plasma concentration profiles of rosuvastatin at steady state.

Notes: (A) Linear scale; (B) semi-logarithmic scale. Error bars denote standard deviations.

Table 4 PK parameters of glimepiride in the SLCO1B1 genotype and CYP2C9 diplotype group (part I)

PK parameters	Glimepiride (G)	Glimepiride + rosuvastatin (GR)	Geometric mean ratio (GR/G)
			Point estimate	95% confidence interval
Total (n=22)
Cmax,ss (ng/mL)	171.4±57.3	176.9±63.1	1.03	0.90–1.17
AUCτ,ss (ng h/mL)	955.8±284.5	1,006.6±369.3	1.04	0.94–1.14
SLCO1B1
Cmax,ss (ng/mL)
TT (n=17)	171.8±61.6	168.4±64.7	0.97	0.80–1.19
TC (n=5)	170.1±45.7	205.9±52.9	1.28	1.01–1.63
P-value#	1.00	0.099
AUCτ,ss (ng h/mL)
TT (n=17)	945.8±300.0	950.8±385.4	0.99	0.86–1.14
TC (n=5)	989.8±250.9	1,196.2±252.4	1.26	1.14–1.38
P-value#	0.94	0.099
CYP2C9
Cmax,ss (ng/mL)
*1/*1 (n=19)	159.7±48.9	174.1±66.3	1.06	0.89–1.26
*1/*3 (n=3)	245.3±59.5	194.8±40.9	0.80	0.03–20.90
P-value#	0.03	0.44
AUCτ,ss (ng h/mL)
*1/*1 (n=19)	884.0±232.3	948.5±363.0	1.04	0.91–1.20
*1/*3 (n=3)	1,410.5±71.7	1,374.3±103.9	0.97	0.33–2.81
P-value#	0.02	0.02

Notes: The values are presented as mean ± SD.

# P-value represents the comparison between the SLCO1B1 or CYP2C9 diplotype groups of glimepiride only and coadministration with rosuvastatin using the Wilcoxon rank-sum test.

Abbreviations: C_max,ss, maximum plasma concentration of the drug at steady state; AUC_τ,ss, area under the plasma concentration–time curve during the dose interval at steady state; PK, pharmacokinetic; SD, standard deviation.

Table 5 Pharmacokinetic parameters of rosuvastatin in the SLCO1B1 genotype group (part II)

PK parameters	Rosuvastatin (R)	Glimepiride + rosuvastatin (GR)	Geometric mean ratio (GR/R)
			Point estimate	95% confidence interval
Total (n=16)
Cmax,ss (ng/mL)	30.9±22.6	29.5±13.5	0.97	0.83–1.14
AUCτ,ss (ng h/mL)	233.3±104.6	205.7±75.7	1.11	1.01–1.23
SLCO1B1
Cmax,ss (ng/mL)
TT (n=13)	31.2±24.4	28.9±14.4	0.99	0.78–1.26
TC (n=3)	29.7±15.9	31.8±10.9	0.80	0.45–1.42
P-value*	1.00	0.59
AUCτ,ss (ng h/mL)
TT (n=13)	234.4±110.1	204.5±81.1	1.12	0.97–1.31
TC (n=3)	227.9±96.2	210.9±58.3	0.99	0.50–1.98
P-value*	0.79	1.00

Notes: The values are presented as mean ± SD.

* P-value represents the comparison between the SLCO1B1 diplotype groups of rosuvastatin only and coadministration with glimepiride using the Wilcoxon rank-sum test. C_max,ss, maximum plasma concentration of the drug at steady state; AUC_τ,ss, area under the plasma concentration–time curve during the dose interval at steady state.

Abbreviations: PK, pharmacokinetic; SD, standard deviation.

Table 6 Incidence of adverse events per treatment group

System organ class Preferred term	Part 1		Part 2
	G	GR	R	GR
Metabolism and nutrition disorders
Hypoglycemia	6 (25.0)	4 (16.7)	0	4 (16.7)
Investigations
Alanine aminotransferase increased	0	1 (4.2)	1 (4.2)	2 (8.3)
Aspartate aminotransferase increased	1 (4.2)	0	1 (4.2)	2 (8.3)
Blood bilirubin increased	0	0	0	1 (4.2)
General disorders and administration site conditions
Chills	0	0	0	1 (4.2)
Face edema	0	0	0	1 (4.2)
Musculoskeletal and connective tissue disorders
Myalgia	0	0	0	1 (4.2)
Skin and subcutaneous tissue disorders
Pruritus	0	1 (4.2)	0	0

Notes: The data are expressed as the number (%) of adverse events. G, treatment group administered a 4 mg glimepiride tablet once per day for 7 days: GR, treatment group administered a 4 mg glimepiride tablet and a 20 mg rosuvastatin tablet concomitantly once per day for 7 days: R, treatment group administered a 20 mg rosuvastatin tablet once per day for 7 days.